Dopamine D3 receptor ligands for the treatment of tobacco dependence

This review considers the potential use of the dopamine D(3) receptor (DRD3) as a novel therapeutic target for the treatment of tobacco dependence. Among the 5 dopamine receptors identified, the DRD3 is located in the nucleus accumbens, ventral tegmental area and amygdala: 3 brain structures that are implicated in the motivational control of drug-seeking behaviour and drug-conditioning processes. Although it has been proposed that modulating dopamine transmission would be effective in the treatment of drug dependence, no validation has been provided in humans so far. Several highly selective DRD3 ligands have recently been evaluated in preclinical models of drug dependence. These ligands act as DRD3 antagonists in vivo and are able to decrease the motivation to take various drugs of abuse and reduce the influence of associated drug-conditioned behaviour. Of note is that these effects have been found with nicotine-seeking behaviour and nicotine relapse in rodents, suggesting a potential use of these ligands for the treatment of tobacco smokers. In contrast to nicotine replacement therapy, varenicline and bupropion (which are currently used for the treatment of smokers), DRD3 antagonists do not seem to produce nicotine-like effects in experimental animals and, therefore, may not substitute for nicotine or alleviate nicotine withdrawal symptoms in human smokers. This behavioural profile, which was also reported recently with cannabinoid CB(1) receptor antagonists, may result from effects on specific brain pathways that express DRD3 receptors and are involved in relapse and conditioning processes. These preclinical studies suggest that the clinical evaluation of DRD3 ligands should be performed with clinical trials designed specifically to evaluate the relapse phenomena.